Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.     

Extracellular matrix gene expression in the left ventricular tissue of spontaneously hypertensive rats.

The aim of this study was to investigate the extracellular matrix gene expression in the hypertrophied left ventricular tissue of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at early and mature ages. Interestingly, with age, a marked increase (+85% and +187% at 25 and 30 weeks of age, respectively, p < 0.01, vs 5 weeks) in matrix metalloproteinase-1 (MMP-1) mRNA levels in SHR and a progressive decrease (-50%, -70%, -78%, -70% at 10, 15, 25 and 30 weeks, respectively, p < 0.01, vs 5 weeks) in WKY were seen. Moreover, mRNA levels were significantly lower in SHR at 5 weeks. The analysis of mRNA expression for the tissue inhibitor of metalloproteinase-1 (TIMP-1) showed a significant increase in WKY (+44% and +44%, vs 15 and 25 weeks, respectively, p < 0.05), whereas there were no significant changes in SHR with development. At 30 weeks TIMP-1 mRNA levels were significantly reduced in SHR. Temporal trends of procollagen alpha1(I) and procollagen alpha1(III) mRNA levels were similar in both strains, but lower levels for procollagen alpha1(III) were found in SHR at 5 and 30 weeks. Although no significant differences were measured between the strains, mRNA levels for fibronectin were found decreased in WKY and increased in SHR with age. The results of the present study suggest an altered balance between collagen deposition and collagen degradation with development in this model of left ventricular hypertrophy and hypertension.     

高血压左心室肥厚与血管紧张素Ⅱ受体的关系

目的探讨自发性高血压大鼠(SHR)左心室肥厚和血管紧张素Ⅱ(AngⅡ)受体的关系。 方法雄性SHR自10周龄始,给予依那普利［enalapril20mg/(kg     

结缔组织生长因子与高血压大鼠心肌纤维化相关性及伊贝沙坦的干预研究

目的探讨结缔组织生长因子(CTGF)在高血压大鼠心肌纤维化发生发展中的作用,以及伊贝沙坦改善高血压所致心室重构和心肌纤维化可能的作用机制。方法20只12周龄雄性自发性高血压大鼠(SHR)随机分为SHR组和伊贝沙坦(IRB)组各10只,IRB组每只大鼠予以伊贝沙坦50 mg.kg-1.d-1灌胃,给药时间12周,同时取10只12周龄雄性Wistar大鼠作为对照组(WKY组),用免疫组织化学的方法对转化生长因子β1(TGF-β1)、CTGF在3组大鼠的左室心肌的分布及表达进行半定量分析;用逆转录-聚合酶链反应检测TGF-β1、CTGF mRNA在心肌表达水平;用MOSSON染色法观察左室心肌胶原形态,图像分析测量胶原容积分数(CVF)和血管周围胶原面积(PVCA)。结果(1)左室重量指数(LVI)、CVF、PVCA在SHR大鼠组明显高于WKY大鼠组(P<0.01);与SHR组比较,伊贝沙坦组则显著降低(P<0.05)。(2)CTGF主要在血管平滑肌和心肌间质中表达,相关分析表明:CTGF与TGF-β1(r=0.562,P<0.05)、CVF(r=0.715,P<0.01)、PVCA(r=0.786,P<0.01)呈正相关;(3)CTGF及其mRNA在SHR组左室心肌中的表达较WKY组明显增强(P<0.05),与SHR组比较,IRB组则明显减少。结论高血压大鼠心室肌CTGF表达增加,伊贝沙坦能抑制高血压大鼠心室肌CGTF表达,且明显改善了高血压心室重构和心肌纤维化。     

Effects of losartan and enalapril at different doses on cardiac and renal interstitial matrix in spontaneously hypertensive rats

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.     

替米沙坦对自发性高血压大鼠左心室重塑的影响

目的探讨替米沙坦对自发性高血压大鼠(SHR)左心室重塑的影响。方法l6只16周龄雄性SHR,随机分为替米沙坦治疗组和SHR空白对照组;另设同源的WKY大鼠8只为正常对照组。治疗组给予替米沙坦10mg·kg-1·d-1灌胃给药,8周后处死动物,测量左心室心肌厚度并称重,计算左心室与体重比(LVW/BW);通过Van Gieson染色法观察左心室心肌胶原变化,对左心室心肌胶原容积分数(CVF)和血管周围胶原面积(PVCA)进行定性和半定量分析;电镜和HE染色观察左室心肌病理及超微结构。结果与WKY组相比,SHR空白对照组的尾动脉收缩压(SBP)、LVW/BW、左室壁厚度、CVF、PVCA、均显著增高(P<0.01);与SHR空白对照组相比,替米沙坦治疗组能有效降低SHR的SBP,改善左心室肥厚(P<0.01),减少心肌间质及心肌小动脉周围的胶原(P<0.01),组织病理及电镜显示,替米沙坦治疗能显著改善SHR左心室重塑。结论替米沙坦能有效降低SHR血压,改善左心室重塑。     

厄贝沙坦对SHR左心室肥厚和心肌纤维化的影响

目的 探讨厄贝沙坦对自发性高血压大鼠(SHR)左心室肥厚(LVH)和心肌纤维化的影响。方法 16只16周龄雄性SHR,随机分为厄贝沙坦治疗组和SHR空白对照组;另设同源的WKY大鼠8只为正常对照组。治疗组予厄贝沙坦15 mg/（kg·d）灌胃给药,8周后处死动物,测量左心室心肌厚度并称质量,计算左心室质量/体质量比(LVM/BM);通过Van Gieson染色法观察左心室心肌胶原变化,对左心室心肌胶原容积分数(CVF)和血管周围胶原面积(PVCA)进行定性和半定量分析;HE染色光镜观察左心室心肌病理变化。结果 与WKY组相比,SHR对照组的尾动脉收缩压(SBP)、LVM/BM、左心室壁厚度、CVF、PVCA、均显著增高(P<0.01);与SHR对照组相比,厄贝沙坦治疗组能有效降低SHR的SBP,改善LVH(P<0.01),减少心肌间质及心肌小动脉周围的胶原(P<0.01)。结论 厄贝沙坦可有效降低SHR血压,减轻心肌纤维化和LVH。     

氯沙坦对自发性高血压大鼠阻力血管结构的影响

目的探讨氯沙坦（Losartan）对自发性高血压大鼠（SHR）阻力血管结构的影响,并观察在高血压血管壁增厚的过程中血管紧张素Ⅱ(AngⅡ)所起的作用。 方法采用6周龄雄性SHR20只,随机分为Losartan治疗组（SHRlos）和对照组（SHR）。另选同系雄性6周龄WKY鼠10只作为正常对照组。6周龄SHRlos给予Losartan30mg/kg/d,溶于饮水灌胃治疗17周。颈动脉插管,心电血流动力学监护仪测定动脉收缩压,应用计算机图象分析,计算血管壁腔面积比,用光镜和透射电镜观察SHR肠系膜动脉三级分支结构的变化;血浆放免法测肾素活性和AngⅡ含量。 结果（1）动脉收缩压（SBP）治疗结束后,SHR     

Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.     

Reduction of cardiac fibrosis decreases systolic performance without affecting diastolic function in hypertensive rats

Pressure-overload left ventricular hypertrophy (LVH) is characterized by an increase in myocyte size and fibrosis. However, it is not clear how each of these components affects hypertensive heart disease (HHD). We have shown in 2 different rat models of hypertension that cardiac fibrosis can be reduced with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an antifibrotic peptide normally present in mammals. To assess how inhibition of fibrosis affects HHD, spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were treated with Ac-SDKP or vehicle. Cardiac systolic and diastolic function were assessed using in vivo pressure-volume (PV) analysis. Left ventricle passive compliance was also determined ex vivo. We found that in SHR, Ac-SDKP normalized left ventricle total collagen content and interstitial collagen fraction without changing myocyte diameter or left ventricle mass. In WKY, collagen did not change significantly after treatment. Ac-SDKP did not affect left ventricle diastolic function, determined in vivo and ex vivo in SHR and WKY, whereas systolic function was significantly decreased in SHR treated with Ac-SDKP and unchanged in treated WKY. We concluded that in adult SHR, reducing left ventricle collagen deposition with Ac-SDKP does not improve diastolic function, whereas it decreases systolic performance. These findings suggest that total left ventricle collagen reduction per se does not necessarily benefit cardiac function. In HHD, other factors besides collagen quantity, such as myocyte hypertrophy and/or collagen type or cross-link, might be targeted to improve cardiac function.     

氯沙坦对自发性高血压大鼠左心室结构改变的实验研究

目的 :探讨氯沙坦 (Los)对自发性高血压大鼠 (SHR)左心室结构的影响。方法 :6周龄Los治疗组 (SHRlos)管饲法给予Los3 0mg kg天。治疗 17周后 ,观察 3组大鼠动脉收缩压 (SBP)、左心室 (LV)壁的厚度、左心室重量 体重 (LVW BW)以及左心室结构的变化 ;血浆放免法测肾素活性和AngⅡ含量。结果 :1 SBP :治疗结束后 ,SHRlos组血压 10 9 15± 11 3 1mmHg( 1mmHg =0 .13 3kPa) ,与对照组 (SHR)血压167 4± 13 0 1mmHg相比明显下降 (P <0 0 1)。 2 SHRlos组的LVW BW、LV壁厚度与SHR组相比明显减少 (P <0 0 1)。SHRlos心肌的超微结构与正常对照组 (WKY)相似。 3 血浆肾素活性在WKY组和SHR组之间无明显差异 (P >0 0 5 )。SHRlos组肾素活性及AngⅡ水平分别高于SHR组 (P <0 0 5 ,P <0 0 1)。结论 :Los能有效地降低SHR的血压 ,具有预防高血压LVH的作用。     

阿托伐他汀改善心室重构作用及其抗氧化机制研究

目的研究阿托伐他汀改善心室重构作用及其抗氧化机制。方法选用16周龄雄性自发性高血压大鼠(SHR)18只,随机分为3组,每组6只:阿托伐他汀组、阳性对照组(缬沙坦组)和阴性对照组(SHR组),另选同周龄雄性Wistar-Kyoto大鼠(WKY)6只作为正常对照组(WKY组),给药6周后测定全心重量(HW)、左心室重量(LVW)、左心室重量指数(LVWI)、心肌羟脯氨酸含量和胶原蛋白含量,透射电镜观察心肌超微结构,同时检测血清和心肌组织超氧化物化酶(SOD)活力、丙二醛(MDA)含量。结果给药6周后,阿托伐他汀组HW、LVW、LVWI、心肌羟脯氨酸含量和胶原蛋白含量明显低于SHR组(P<0.05);电镜显示阿托伐他汀组心肌与SHR对照组比较,肌原纤维较清晰,排列整齐,横纹清楚,间质胶原纤维无明显增生;阿托伐他汀组血清和心肌组织SOD活力明显高于SHR组、MDA含量明显低于SHR组(P<0.05)。结论阿托伐他汀有明显改善心室重构的作用,其机制可能与其抗氧化作用有关。     

Changes in cardiac energy metabolism during early development of female SHR

We investigated effects of hypertension and early development on myocardial energy metabolism as reflected by maximal enzyme activities, glucose transporter content, and endogenous substrates in female Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Left ventricular hypertrophy and systolic hypertension were evident in SHR at 6 weeks of age and these differences increased at 14 and 22 weeks of age. 3-Hydroxyacyl-CoA dehydrogenase (HOAD) activity in the left ventricle was 18% lower in 6-week-old rats than both 14- and 22-week-old rats, but not different between WKY rats and SHR. Hexokinase activity was 15% lower in 6-week-old SHR than WKY rats and decreased progressively with age in both strains. Glucose transporter (GLUT) 1 content was nearly twofold greater in 6-week-old rats than both 14- and 22-week-old rats. We found no difference in citrate synthase activity or GLUT4 content among groups. Glycogen concentration was 44% lower in SHR than WKY rats, whereas triglyceride was slightly (16%) higher in SHR than WKY rats. Older animals had higher levels both glycogen and triglyceride than younger animals. We conclude that the left ventricle of both SHR and WKY rats may change from predominantly glucose to fatty acid oxidation for energy production during early development.     

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30?mg?kg(-1) per day losartan, an angiotensin receptor blocker, or with 20?mg?kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.     

Effects of chronic hypertension and left ventricular hypertrophy on the extent of infarct expansion in rats

Left ventricular hypertrophy is an adaptive response to long standing hypertension. However, the influence of left ventricular hypertrophy with hypertension on extent of infarct expansion has not been studied. We compared the effects of left ventricular hypertrophy with hypertension on infarct expansion in spontaneously hypertensive rats (SHR, n = 76), Wistar-Kyoto rats (WKY; n = 46) and spontaneously hypertensive rats treated with delapril, an angiotensin converting enzyme (ACE) inhibitor (SHRD; n = 39). The survival rates at 7 days after myocardial infarction were 41%, 24%, and 46% for WKY, SHR, and SHRD. The survival rate of SHR was significantly lower than those of both SHRD and WKY (P < .05). In the surviving rats (18 SHR, 19 WKY, 18 SHRD), both left ventricular cavity area (LCVA) and the infarct segment length per the noninfarct segment length (FW/IVS), measured as indices of left ventricular dilation, were significantly less in SHR and SHRD than in WKY, and the thickness of the left ventricular free wall (Wth), used as an index of left ventricular thinning, was significantly higher in both SHR and SHRD than in WKY (P < .01). However, there was no significant difference in FW/IVS, LCVA, and Wth between SHR and SHRD. Hemodynamic findings 1 week after coronary occlusion demonstrated that all rats were in heart failure, and there were no significant differences in hemodynamics among the three groups. In conclusion, our findings showed that hypertrophy with hypertension reduced infarct expansion, but that reduction of blood pressure by ACE inhibitor did not reduce infarct expansion more than hypertrophy did. However, this finding suggests that an ACE inhibitor may improve the rate of survival of patients with left ventricular hypertrophy with hypertension.     

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.     

Blockade of angiotensin II provides additional benefits in hypertension- and ageing-related cardiac and vascular dysfunctions beyond its blood pressure-lowering effects

OBJECTIVES: To assess the blockade of the renin-angiotensin system (RAS) or blood pressure-lowering on cardiovascular functions in hypertensive and ageing animals. METHODS: Male spontaneously hypertensive rats (SHR) and their normotensive counterparts, Wistar-Kyoto rats (WKY), at the ages of 3-4 (young), 34-35 (adult) and 74-75 (old) weeks were treated with an angiotensin II type 1 receptor antagonist, losartan (25 mg/kg) or a combination of a smooth muscle relaxant and a diuretic [H/H, hydralazine (50 mg/kg) plus hydrochlorothiazide (7.5 mg/kg), respectively] for 8 weeks. Each experimental group contained 10 SHR and 10 WKY, where equal numbers of untreated animals served as controls. RESULTS: Compared to age-matched WKY groups, SHR groups possessed, on average, 48 +/- 7 mmHg and 57 +/- 16 mmHg (P < 0.05) higher systolic blood pressure and left ventricular developed pressures, respectively. The values of these parameters were significantly lowered in both strains by both treatment regimens. SHR had higher heart rates, which were increased by H/H treatment selectively in adult and old animal groups of both strains. Both treatment regimens enhanced KCl-mediated, that is, receptor-independent, aortic contractile responses and bradykinin-mediated coronary vasodilatation in adult and old WKY and SHR age-groups. Although both therapies augmented endothelium-dependent and endothelium-independent relaxant responses in young and adult, but not in old, SHR aortas to the levels observed in age-matched WKY, these beneficial effects were more prominent with losartan. Moreover, losartan reduced heart to body weight ratio in all SHR age groups, and selectively in the old WKY group. CONCLUSIONS: Blockade of RAS provides a better protective effect on cardiovascular function compared to sole reduction of blood pressure, and the efficacy of antihypertensive treatment is dictated by age and the hypertensive stage of the animals.